Angiogenesis is a course of the growth of a new blood vessel in the existing vascular system. It is a necessary physiological change in embryonic development, wound healing, tissue regeneration and tissue repair. However, it is also a pathological basis for many systemic and topical diseases. Said systemic diseases include neovascular eye diseases, tumor angiogenesis, rheumatic arthritis, psoriasis, etc.
Angiogenesis involves a complicated course with multiple steps, including proliferation, migration and invasion of vascular endothelial cell and formation of lumen, etc. Angiogenesis is strictly controlled by the balance between proangiogenic factors and anti-angiogenic factors. Breaking said balance may initiate a cellular signal of angiogenesis, leading to pathological neovascular generation. Vascular endothelial growth factor (VEGF) is a central induction mediator of this complicated angiogenesis cascade, which specifically acts on the vascular endothelial cell.
Human VEGF gene consists of 8 exons and 7 introns, with a length of about 14 kb. The
VEGF family contains at least 4 members due to different splicing modes of RNA, which are VEGF121, VEGF165, VEGF189, and VEGF206. The VEGF165 is the primary isomer.
The neovascular eye diseases are a type of diseases causing blindness with high incidence which have wide destructiveness and may involve the whole eyeball, including age-related macular degeneration, diabetic retinopathy, corneal infection, and neovascular glaucoma. Lesions secondary to ocular neovascularization, such as bleeding, exudation and fibrosis, also seriously affect the vision quality and the quality of life of the patient. However, methods for treating these kinds of diseases currently are limited, the effects are not so fine, and the safety needs to be further confirmed.
When developing effective inhibitors of neovascularization, the specificity of the ocular drugs should be sufficiently considered.
Firstly, there are many anatomical and functional barriers in eyes. Systemic administration usually cannot produce topically sufficient drug concentration in ocular tissue due to the blood-aqueous humor barrier and blood-retina barrier. In topical administration, such as injection in vitreous cavity, the macromolecule larger than 76.5 kDa theoretically is difficult to penetrate the retina to act on the retinal and choroidal neovascularization.
Secondly, the solubility of the drugs in the hydrophilic tears, aqueous humor, and vitreous humor is positively correlated to their effects.
Thirdly, for the above major reasons, the bioavailability of ocular drugs is very low. To improve it, the concentration of drugs administered may be increased. However, compounds for treating neoplastic neovascularization exhibit obvious toxicity, so that high dose cannot be used in either systemic or topical administration.
Fourthly, currently a series of relatively safe endogenous inhibitors of neovascularization, such as angiostatin consisting of plasminogen Kringle domains 1-4, have been demonstrated to obviously inhibit growth of vessel blood-dependent tumor. However, due to their relative large molecular weight and complicated spatial conformation, these inhibitors have disadvantages, such as complicated recombinant expression and purification processes in preparation, residual endotoxin and so on.
Therefore, there is an urgent need in developing inhibitors of neovascularization, which are small molecules, safe and effective, and compatible with eyeball tissues.